Background

The interplay between dietary composition , gut microbiota and microbe-generated metabolite is receiving increasing attention. This is also interesting for CV risk management, as dietary habits are considered a modifiable risk factor. Trimethylamine N-oxide (TMAO) is a small, organic, gut

Preclinical studies suggest a mechanistic link between TMAO and CVD [2-4]. TMAO may promote atherosclerosis through increased expression of macrophage scavenger receptors and formation of foam cells in the artery wall [3]. Moreover, non-lethal inhibition of microbial production of TMAO in mice has been shown to diminish atherosclerotic lesions [5]. TMAO has also been associated with (reverse) cholesterol transport and bile acid composition [2, 6-9]. Moreover, high levels of TMAO have also been found to promote endothelial dysfunction, exacerbate platelet reactivity, and to enhance thrombosis, affect lipid metabolism and inflammatory response [4, 10-12].

The potential impact of TMAO as a novel biomarker for CVD and its prognostic role in disease progression has not yet been systematically addressed. Plus, a potential causal role is debated, for instance because fish as an important dietary source of TMAO is confusing, since fish consumption has been shown to be protective for CVD.

This is the first systematic review and dose-response meta-analysis of published studies to quantitatively assess the association between TMAO plasma levels and CV outcomes (mortality and MACCE: death, MI and stroke). 17 Studies with at least 100 included patients with CVD, with TMAO plasma levels reported as either categorical or continuous variable were included, with data on 26167 subjects. Mean follow-up was 4.3 ± 1.5 years.

The significant association with mortality also persisted after stratification for geographical location of enrollment (USA, Europe, rest).

The dose-response meta-analysis showed an RR for all-cause mortality of 7.6% higher risk per each 10 µmol/L increment of TMAO (summary RR: 1.07, 95%CI: 1.04-1.11, P<0.0001). There was evidence for a non-linear association (P non-linearity <0.00001).

The incidence of MACCE was significantly higher in those with high vs. low TMAO levels (HR: 1.67, 95%CI: 1.33-2.11, P<0.0001).

Various sensitivity analyses confirmed the observed associations.

Meta-regression analysis only revealed coronary artery disease as a potential effect modifier, in the sense that studies with a higher percentage of CAD patients showed an increase of the association between high TMAO levels and mortality.

Conclusion

This analysis in a large population shows that high-circulating concentrations of TMAO were associated with higher risk of all-cause mortality and MACCE. A dose-dependent, direct association was observed, and the observed association was consistent across subgroups and all study populations. The shape of the dose-response association requires further characterization.

Surprisingly, observations were consistent for patients with or without CKD, although high circulating TMAO levels have been described in CKD. Nor did geographical localization of populations affect the primary outcome, although dietary patterns may vary, although most studies were conducted in the USA and Europe.